Laboratory of Neuro-Oncology, Tianjin Neurological Institute, PR China.
Brain Res. 2010 Dec 17;1366:27-37. doi: 10.1016/j.brainres.2010.10.032. Epub 2010 Oct 20.
Malignant gliomas are the most common type of intrinsic central nervous system (CNS) tumors with high mortality and morbidity. β-catenin is overexpressed in human glioblastoma and knockdown of β-catenin inhibits glioblastoma cell proliferation and invasive ability, and induces apoptotic cell death. Furthermore, treating the nude mice carrying established subcutaneous LN229 gliomas with siRNA targeting β-catenin intratumorally also delayed the tumor growth. However, the mechanisms of down-regulation of β-catenin that represses glioblastoma malignancy behavior remain to be elucidated. We utilized text-mining of MEDLINE abstracts with natural language processing to establish the β-catenin biologic association network, and identified several interactions of this network with the EGFR pathway. In both in vitro and in vivo studies, our results confirmed down-regulation of β-catenin induced reduced expression of EGFR, STAT3 and AKT1 mRNA and protein, besides, the level of phosphorylated Akt also decreased. A similar reduction in expression of CyclinD1, MMP2 and MMP9, downstream genes of the EGFR pathway, was observed. These results suggest that the Wnt/β-catenin pathway regulates glioma cell proliferation and invasion, in part via the EGFR pathway.
恶性神经胶质瘤是最常见的原发性中枢神经系统 (CNS) 肿瘤，死亡率和发病率都很高。β-连环蛋白在人类神经胶质瘤中过度表达，β-连环蛋白的敲低抑制神经胶质瘤细胞的增殖和侵袭能力，并诱导细胞凋亡性死亡。此外，用针对β-连环蛋白的 siRNA 对携带皮下 LN229 神经胶质瘤的裸鼠进行瘤内治疗也延迟了肿瘤生长。然而，下调β-连环蛋白抑制神经胶质瘤恶性行为的机制仍有待阐明。我们利用 MEDLINE 摘要的文本挖掘和自然语言处理建立了β-连环蛋白的生物学关联网络，并确定了该网络与 EGFR 通路的几个相互作用。在体外和体内研究中，我们的结果证实下调β-连环蛋白诱导 EGFR、STAT3 和 AKT1 mRNA 和蛋白的表达减少，此外，磷酸化 Akt 的水平也降低。还观察到 EGFR 通路下游基因 CyclinD1、MMP2 和 MMP9 的表达减少。这些结果表明 Wnt/β-连环蛋白通路通过 EGFR 通路调节神经胶质瘤细胞的增殖和侵袭。
